ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.1997A>T (p.Asp666Val) (rs863225147)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201632 SCV000256275 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research
GeneDx RCV000414742 SCV000491090 likely pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing p.Asp666Val (D666V) (GAT>GTT): c.1997 A>T in exon 14 of the AHI1 gene (NM_017651.4) The D666V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these population. The D666V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV001051208 SCV001215351 pathogenic Joubert syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 666 of the AHI1 protein (p.Asp666Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 26092869, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AHI1 protein function. For these reasons, this variant has been classified as Pathogenic.

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